Spatially confined IL-12 programs CAR-NK through mTORC1 to coordinate antitumor immune networks
Abstract Solid tumors evade immunotherapy because of immunosuppressive microenvironments that limit immune cell persistence and function. Although interleukin-12 (IL-12) potently activates antitumor immunity, its clinical use has been constrained by systemic toxicity. Here we engineered a CAR natural killer (NK) cell platform that integrated IL-12 signaling to enhance antitumor immunity. IL-12 signaling synergized with CAR activation to sustain mTORC1 activity through convergent Ras-ERK and PI3K pathways, promoting metabolic fitness, autonomous expansion, and sustained effector function. IL-12 also activated bystander NK cells, T cells, and macrophages to remodel the tumor microenvironment. To improve safety, IL-12 was tethered to a collagen-binding A3-domain, restricting its activity to the extracellular matrix and limiting systemic exposure. In ovarian and pancreatic cancer models, matrix-anchored IL-12 CAR NK cells expanded without exogenous cytokines and achieved durable tumor control. These findings suggest that mTORC1-mediated integration of CAR and cytokine signaling can enhance immune fitness and overcome immunosuppressive tumor microenvironments.
Authors
- Junning Wang (ORCID: https://orcid.org/0000-0002-5559-9343)
- Grace Caroline Birch
- Jerome Ritz (ORCID: https://orcid.org/0000-0001-5526-4669)
- Khanhlinh Dinh (ORCID: https://orcid.org/0009-0007-6108-4147)
- Michal Sheffer (ORCID: https://orcid.org/0000-0001-5934-9950)
- Marco Campisi (ORCID: https://orcid.org/0000-0002-9288-5285)
- John Koreth
- Seema Chugh (ORCID: https://orcid.org/0000-0003-1486-0725)
- Daniel E. Michaud (ORCID: https://orcid.org/0000-0001-7816-3924)
- Jianzhu Chen (ORCID: https://orcid.org/0000-0002-5687-6154)
- Catherine J. Wu (ORCID: https://orcid.org/0000-0002-3348-5054)
- Toni K. Choueiri (ORCID: https://orcid.org/0000-0002-9201-3217)
- Cloud Peter Paweletz (ORCID: https://orcid.org/0000-0002-2287-5663)
- Ursula A. Matulonis (ORCID: https://orcid.org/0000-0002-3103-6992)
- David Allen Barbie (ORCID: https://orcid.org/0000-0002-5422-4275)
- Rizwan Romee (ORCID: https://orcid.org/0000-0001-9077-4736)
- Shikha Gupta (ORCID: https://orcid.org/0000-0002-9416-1360)
- Robert J. Soiffer (ORCID: https://orcid.org/0000-0002-5810-1192)
- José A. Cancelas (ORCID: https://orcid.org/0000-0002-1291-7233)
- Quang‐Dé Nguyen (ORCID: https://orcid.org/0000-0002-9043-4413)
- Andrew J. Aguirre (ORCID: https://orcid.org/0000-0002-0701-6203)
- Guillermo Nicolás Dalton (ORCID: https://orcid.org/0000-0002-3892-807X)
- Prafulla C. Gokhale (ORCID: https://orcid.org/0000-0002-1974-5921)
- Rebecca L. Porter (ORCID: https://orcid.org/0000-0002-4848-1275)
- Andreia Maia (ORCID: https://orcid.org/0000-0002-7860-6219)
- Mubin Tarannum (ORCID: https://orcid.org/0000-0002-4440-1565)
- Eden Bobilev
- Yang Gao (ORCID: https://orcid.org/0000-0001-6657-7951)
- Shaobo Yang (ORCID: https://orcid.org/0009-0006-5257-6775)
- Jennifer L. Guerriero (ORCID: https://orcid.org/0000-0002-2104-5457)
- Suthakar Ganapathy (ORCID: https://orcid.org/0000-0003-3828-5382)
- Ian Gillanders
- Maily Nguyen
- Mila Stanojevic
- Fuguo Liu (ORCID: https://orcid.org/0009-0005-2850-4184)
Institutions
- University of Pittsburgh (US)
- Dana-Farber Cancer Institute (US)
- Dana-Farber/Harvard Cancer Center (US)
- Cincinnati VA Medical Center (US)
- Dana-Farber Brigham Cancer Center (US)
- University of Cincinnati (US)
- Massachusetts Institute of Technology (US)
Publication Details
- Journal
- Cancer Discovery
- Published
- 2026-09-29
- DOI
- https://doi.org/10.1158/2159-8290.cd-26-0509
- Primary Topic
- Immune Cell Function and Interaction
- Type
- article
- Field-Weighted Citation Impact
- 0.00